Practical application of digital therapeutics in people with mood disorders

Digital therapeutics (DTx) offer evidence-based digitally-delivered high quality standards applications and/or softwares in the prevention, management and treatment of several medical conditions, including mood disorders. Nowadays, there are only three DTx officially approved by the Food and Drug Administration for mental conditions and there are still very few DTx developed in the context of mood disorders. The current comprehensive overview aims at providing a summary of currently published studies on DTx clinical applications in major depressive disorder (MDD), depressive symptomatology and bipolar disorder (BD), by using PubMed/MEDLINE and Scopus databases. Fifteen studies have been selected (10 on DTx in depressive symptomatology and/or MDD; 4 on BD; 1 on MDD and BD). Literature on DTx in mood disorders is still lacking, being mostly constituted by feasibility and acceptability rather than efficacy/effectiveness outcomes, particularly in BD. More studies focused on MDD compared to BD. Most DTx on MDD have been developed based on cognitive behaviour therapy interventions while on BD are based on psychoeducation. All studies assessing symptom severity improvement pre- vs. postinterventions demonstrated a significant postintervention improvement. Therefore, despite the preliminary encouraging results of studies here retrieved, their methodology is still too heterogeneous to allow comparisons and the generalizability of their findings. Further studies are warranted, in more larger samples involving multiple sites, including measures of both specific symptom effects as well as acceptability, feasibility and effectiveness in the real-world settings.


INTRODUCTION
According to the World Health Organization (WHO), about one in eight people nowadays suffer from mental disorders, mostly represented by mood (particularly depression) and anxiety disorders, further increased due to the coronavirus disease 2019 (COVID-19) pandemic [1].In WHO's Comprehensive Mental Health Action Plan 2013-2030 it is planned to boost mental health promotion and prevention strategies, as well as to strengthen the mental health information systems as well as digital opportunities in mental disorders [1].Indeed, digital psychiatry may offer different prevention, management, and treatment interventions for a broad spectrum of physical, mental, and behavioural conditions [2].In the field of mental health, many digitally-delivered interventions have been developed for delivering effective and feasible treatments for several mental conditions, including mood disorders [2].Indeed, few digital mental health interventions are effectively supported by scientific and clinical evidence, such as the digital therapeutics (DTx).
The term DTx was firstly introduced by Joseph Kvedar in 1995, to identify all evidence-based therapeutic interventions driven by software to prevent, manage or treat a medical disorder or disease [3].DTx uses digital implements such as mobile devices, apps, virtual reality, the Internet of Things (IoT), wearable sensors and so forth to spur patients' behavioural changes.DTx can be used as a standalone therapy or in combination with pharmacological treatment, integrating software-and algorithm-based technological innovation with drug treatment [2,3].DTx are classified as Medical Devices and, hence, they need to be specifically developed with high scientific quality and validated standards through randomized controlled clinical trials (RCTs), as for drug-based therapies [3].More specifically, DTx are classified in two categories: SaMDs (i.e., 'software as a medical device') and SiMDs (i.e., 'software in a medical device').SaMDs indicate a software that functions as an actual medical device, while SiMDs is a software that is included within a medical device for treating a specific medical condition [4].When a SaMD or SiMD is embedded within a smartphone it is called a 'mobile medical app' (MMA) [5].
Furthermore, DTx by definition are also supported by clinical evidence coming from real-world outcomes, as well as approved by regulatory agencies [such as the Food and Drug Administration (FDA)], prescribed by physicians and (only in some countries) reimbursed by national health systems (NHS) and/or private insurances [6].At the European level, there are not still specific legal regulations on DTx assessment or to guarantee their safety and the integrity of data collected.Currently the European Medicines Agency (EMA) and the European Commission (EU) are starting to explore DTx as therapeutic solutions.At national level, the new German Digital Healthcare Act (DiGA) regulates specific requirements for the use of DTx (i.e., quality, security and data protection) and France is moving towards a similar act [6].In the UK, the National Institute for Health and Care Excellence (NICE) set up a working group under the guidance of the NHS to support regulatory boards in identifying which types of evidence are most relevant to the assessment of DTx [6].To date, three DTx products have been recommended by NICE (but not yet approved): 'Deprexis' (an interactive medical device for unipolar depression); 'Space from Depression' (an online programme for the treatment of depression); and BDD-NET (an online programme for treating moderate-to-severe body dysmorphic disorder) [7][8][9] (Table 1).While in the USA, FDA has an active precertification program on DTx in place since 2017.However, FDA currently approved only three DTx in the field of mental health: reSET (a computerized behavioural therapy device for substance use disorders); Somryst (a computerized behavioural therapy device for treating chronic insomnia); and Endeavour (a serious game for young patients with ADHD) [10 2).DTxs could represent effective tools in the prevention, management and treatment of mood disorders [13].However, given the limited availability of DTx officially approved by abovementioned regulatory bodies, there is the need to provide a comprehensive overview on currently available studies aiming at investigating the practical

METHODS
A comprehensive literature review has been carried out here in order to better deepen the practical applications of DTx in mood disorders, including peripartum depression.Studies were identified searching the electronic databases MEDLINE/ PubMed and Scopus.A combined search strategy of free text terms and exploded MESH headings for the topics of Digital Therapeutics (DTx) and Mood Disorders as following: (((Digital Therapeutics[Title/ Abstract]) OR (DTx[Title/ Abstract])) AND ((Mood Disorder[Title/Abstract]) OR (Depression[Title/ Abstract]) OR (Bipolar Disorder[Title/ Abstract]))), without time restrictions, through September 29, 2023.In addition, further studies were retrieved from reference listing of relevant articles and consultation with experts in the field and or manual search.We limited the search to only English-written studies.The following exclusion criteria have been applied: not human studies; studies on DTx without data on its application in mood disorders; studies on digital mental health but not specifically addressed to DTx; studies on DTx applied in mood disorders in comorbidity with physical and/or other mental conditions; studies discussing only protocols without clinical data; studies on already NICE recommended DTx for mood disorders.Identified studies were independently reviewed for eligibility by two authors (G.L. and L.O.) in a two-step-based process; a first screening was performed based on title and abstract while full texts were retrieved for the second screening.At both stages, disagreements by reviewers were resolved by consensus.Data were extracted by two authors (G.L. and L.O.) and disagreement was resolved by a third author (U.V.) using an ad-hoc developed data extraction spreadsheet.With the initial set of keywords, by integrating all databases, some 1,135 studies were identified.After screening and selection by using inclusion criteria, only 20 articles were selected.Of these 15 relevant studies were finally included.Table 3 summarizes the main findings of studies here retrieved.Findings have been discussed according to different diagnostic groups (i.e., studies concerning MDD, BD or both).

Depression
Iacoviello et al. [14] developed a cognitive-emotional training intervention for MDD, named 'Emotional Faces Memory Task' (EFMT), consisting of to deliver stimuli that are designed to engage the patient in a manner that improves their attention function.In a closedloop system, the adaptive SSME algorithms automatically adjust the difficulty level for a personalized treatment experience that is tailored to the needs of each individual patient.
Delivered through a video game experience which leverages art, music, storytelling, and reward cycles to keep patients engaged.The basic program inputs are steering, which is accomplished by using the internal accelerometer to measure the degree to which the mobile device is tilted, and tapping, which is accomplished using the touch screen to measure correct and incorrect targeting.The basic outputs are a visual display of the game progression along with audio, which is accomplished by using the internal high-resolution display and internal speaker.
Practical application of digital therapeutics in people with mood disorders Orsolini et al.Bower et al. [16] developed 'ADvisors', a digital intervention prototype, specifically aimed to assist patients during discontinuation of antidepressant therapy.This intervention is designed to educate patients about medication taken, especially by providing information regarding side effects and discontinuation symptoms.These types of activities would also allow for greater control by physicians over the patient's health.
Venkatesan et al. [6] conducted a study to investigate the effectiveness of 'Vida Health's' app-based CBT program.Specifically, the app allows patients to connect with a therapist, who provides a set of activities and goals based on the progress of therapy each week.The results demonstrated a significant reduction in depressive symptomatology, which maintained stability over time.
Gould et al. [17] investigated the efficacy of the 'Meru Health' app addressed to adults and older adults with depressive symptomatology.The app works by delivering CBT and mindfulness-based therapy by trained psychotherapists on a daily basis through informative materials and videos.It also allows patients to ask for an asynchronous conversation with the therapist and a group discussion.Findings highlighted a good feasibility and a significant reduction in depressive and anxiety symptomatology.
Tang et al. [18] developed the app 'MamaLift' addressed to postpartum depression, consisting of a self-guided intervention that can be delivered independently or with the support of a therapist.Each day it is proposed to the patient a self-guided program based on CBT, IPT, dialectical behaviour therapy (DBT) and behavioural activation therapy (BAT) through videos, audios and text formats.Findings found a high level of satisfaction, feasibility and usability by the patients.
Kulikov et al. [19] developed the 'Spark' app consisting of a self-guided 5-weeks CBT, specifically addressed to adolescents aged 13-18 patients.Outcomes reported a high level of engagement and satisfaction by patients, as well as a significant reduction in depressive symptoms.
Gual-Montolio et al. [20] described the effects of 'My EMI', and app to promote emotional well being in a sample of adults with emotional disorders, including depressive symptomatology.The intervention is based on Measurement-Based Care (MBC), which consists of regular monitoring of patients, periodic feedback to the therapist (or both therapist and patient), and adaptation of the intervention based on these feedbacks.
Chatbots are software applications designed to replicate human conversations, enabling users to interact with digital devices as if they were engaging with a genuine person [21].Fitzpatrick et al. [22] used a chatbot, Woebot, in young adult patients with depressive symptoms.Suharwardy et al. [23] conducted studies on the use of Woebot in the context of postpartum depression.This intervention equips patients with tools from CBT and interpersonal therapy (IPT) to manage mood and anxiety.Both studies reported a significant depressive symptomatology reduction, although Suharwardy et al. [23] did not include only women with confirmed diagnosis of postpartum depression.

Bipolar disorder
Depp et al. [24] conducted a study using a mobile intervention, called 'PRISM', which provides BD patients with information from the BD psychoeducational intervention in a self-managed approach, without the intervention of a therapist.Through a series of mood questions, the app also creates a mood chart to monitor mood trends.The results showed a reduction in depressive symptoms but not of manic symptoms.Dodd et al. [25] and Lobban et al. [26] conducted two studies based on 'Enhanced Relapse Prevention' (ERPonline) addressed to BD subjects.It is a selfdirected web-based intervention that allows people to create a model of their mood fluctuations, allowing them to recognize and manage triggers of new episodes and develop new effective coping strategies.The intervention has been described by patients as accessible, relevant and straightforward [25,26].
Jonathan et al. [27] and Dopke et al. [29] developed a self-management 'LiveWell' app for BD patients, which provides information about disorder and learns specific skills to manage mood fluctuations and recurrences.At the same time, it allows the development of a Wellness plan to reduce the risk of relapse and the management of signs and symptoms in acute phases.It also allows monitoring of treatment adherence, sleep duration, and wellness [27,28].

Depression and bipolar disorder
Cho et al. [29] conducted a study on patients with major depressive disorder and bipolar disorder constituted by multiple digital interventions.Each patient was asked to fill out a daily eMood chart and use a wearable daily activity tracker.An app named 'Circadian Rhythm for Mood' collects all passive and active data to predict mood trends and identify specific subject's relapse variables.'Circadian Rhythm for Mood' demonstrated to significantly reduce the number and duration of depressive and manic episodes, promoting also the development of healthy protective behaviours.

DISCUSSION
Overall, there is an urgent public health need for more evidence-based, high quality, more portable and accessible, as well as more effective and clinically validated DTx in the real-world settings for MDD and BD.Web-based interventions, particularly DTx, may offer the potential to broaden access, reduce waiting times, delivery costs and stigma as well as improve quality through standardized and clinically validated delivery.Current retrieved literature on DTx applications in the field of mood disorders appear still lacking, being mostly constituted by feasibility and acceptability studies rather than efficacy and/or effectiveness studies.There are more studies specifically addressed to MDD, even though mostly recruited subjects with depressive symptomatology, not necessarily with a MDD diagnosis (Table 3); being more represented by adult subjects with only one study addressed to young adults [22], only one study recruiting adolescents [19] and one study included older adults [17].Two studies were carried out on women at-risk for postpartum depression (PPD) [18,23].Moreover, most studies on MDD were conducted in the USA and in a single-site and recruited a small sample size (with less than 100 recruited subjects) (Table 3).Most DTx on MDD or depressive symptomatology have been developed based on CBT interventions, with one study based on EFMT [14] and the two only studies on PPD which integrate both CBT and IPT [18,23].While only four are the published studies evaluating DTx on BD samples, with mostly recruiting a relatively small sample size (20 recruited subjects) and based on feasibility and/or acceptability outcomes as well as psychoeducational-based interventions (Table 3).Most of the studies on BD were conducted in the USA or UK and on adult subjects.The only study recruiting both MDD and BD individuals was conducted in Korea and investigated the efficacy and effectiveness of DTx in both samples [29].Overall, all studies assessing symptom severity improvement pre-vs.postinterventions (both addressed to MDD or BD individuals) demonstrated a significant postintervention improvement, even though only in one study it was conducted also a follow-up evaluation over the time to investigate whether their improvements were long-term maintained [29].
Therefore, there are several limitations to be acknowledged in the current review.Firstly, most studies recruited small sample sizes, not sex-and/or -age homogeneous groups, with heterogeneous methodology regarding inclusion criteria and assessment tools, which may limit the generalizability of their findings.Secondly, most studies tested the only feasibility and level of acceptability of DTx without posing as the primary outcome the clinical efficacy and/or effectiveness of the interventions on MDD and/or BD subjects.Thirdly, most studies have been carried out as RCT without evaluating their feasibility in a 'real-world' setting or in a large sample of more heterogeneous individuals.Fourthly, most studies did not evaluate the attrition rate ('not-attrition bias') and mostly were single-site studies, conducted in the USA or UK.Furthermore, most studies did not evaluate follow-up data to evaluate the sustainability of results over the time.
Furthermore, despite the potential and encouraging results of DTx studies here retrieved, their methodology is still too heterogeneous to allow comparisons and the generalizability of their findings.Finally, further studies are warranted, in more larger samples involving multiple sites, including measures of both specific symptom effects as well as acceptability, feasibility and effectiveness in the real-world settings.Moreover, more studies should be conducted to investigate DTx in MDD and BD by recruiting different age-groups (i.e., adolescents vs. young adults vs. adults vs. elderly) in order to compare whether it may differ from the findings based on the different target population.Furthermore, studies assessing depressive symptomatology should be implemented and verified in the MDD population in order to evaluate their efficacy, effectiveness as well as feasibility and acceptability may differ according to the symptom severity and diagnosis.Finally, further studies should be carried out in order to develop and implement more DTx interventions focussed on CBT, IPT and Interpersonal and Social Rhythm Therapy (IPSRT) on BD population.

Table 1 .
DTx are evidence-based digital therapeutic interventions to prevent, manage or treat a medical disorder.Characteristics of NICE-recommended DTxs for use in the field of mood disorders

Table 2 .
Characteristics of FDA-approved DTxs in the field of mental health

Table 3 .
Characteristics of the included studies

Table 3 (
Continued)Practical application of digital therapeutics in people with mood disorders Orsolini et al.